Process for the preparation of 17alpha-hydroxy-16alpha-methyl-20-keto steroids of the 5alpha-series



United States Patent PR 12553 FOR THE PREPARATION OF 17a-HY-DRQXY-la-METHYL 20 KETO STEROIDS OF THE Soc-SERIES Gordon HanleyPhiliipps and William Graham, Greenford, Gordon Ian Qregory, ChalfontSt. Peter, and Joseph Elias, Golders Green, London, England, assignorsto Glaxo Laboratories Limited, Greenford, Englmd, a British company NoDrawing. Filed July 18, 1960, Ser. No. 43,290

Claims priority, application Great Britain July 20, 1959 3 Claims. (Cl.260397.45)

This invention is concerned with improvements in or relating to thepreparation of steroid compounds, and, more particularly, with thepreparation of Mot-methyl steroid compounds possessing anti-inflammatoryand/or adrenocortical activity, analogues thereof and intermed atestherefor.

Various steroids having a methyl group in the aor ,8- configuration inthe lo-position have been described as having important pharmacologicalproperties and, in ge eral, are said to possess more pronouncedanti-inflammatory properties and less undesirable side efiects than thecorresponding steroids not possessing the l6-methyl group. Thepreparation of such compounds has hence become of importance.

The preparation of 16-methyl steroids from ll-lceto steroids of the5,8-pregnane series has been described. However, some substances readilyavailable and hitherto used as starting materials for the manufacture ofadrenocortical hormones are members of the Six-series, an importantexample of such a substance being heccgenin.

It is thus a general object of the present invention to provide aconvenient process for the production of steroids of the Set-series,characterised by possessing a 17mhydroxy-lfia-methyl-ZO-keto structure,from corresponding steriods 0f the Set-series possessing al6-methyl-l6-en- ZO-lreto structure. The production of correspondingcompounds in which the methyl group at position 16 has thefl-configuration is the subject of copending application No. 43,286 ofeven date herewith.

Steroid compounds of the Su-pregnane series possessing a lmethyl-l6-en-20-keto structure can be prepared from raw materials suchas hecogenin in various known ways dependent on the nature of theremaining portions of the molecule. Thus, for example, hecogenin acetatecan be converted in several steps to form 3B-acyloxy5u-pregna- 9(11):16-dien-20-ones (cf. Djerassi et al., J. Org. Chem. 1951, 16, 1278, andCallow and James J.C.S. 1956, 4739) which can be converted to3,8acyloxy-16-methyl-5upregna-9(ll):l6-dien-20-ones, for example by themethods described in application No. 43,095, filed July 15, 1960. Theselast-mentioned intermediates are analogous to intermediates hithertoused in the synthesis of anti-infiammatory compounds. Other similarintermediates in the Se-pIegnane series containing 16-methyl-20-ketostructures are the corresponding 9:11-dichloro compounds and thecorresponding compounds containing a saturated Ring C and an oxygenfunction at position 11. It is hence a specific object of the presentinvention to provide a means of introducing 17a-hydroxy groups inintermediates of the kind just mentioned of the Sa-pregnane series.

In principle, the process of the present invention involvesrearrangement of a 16:l7-epoxy-l6fi-methyl-20- keto steriod (which canreadily be obtained by epoxidation of a A -steroid) followed byhydrogenationof the product to a 17tz-hydroxy-16a-methyl-20-ketocompound.

The 17a-hydroxy-16a-methyl-20-keto products according to the inventioncan be converted into compounds having anti-inflammatory and/ora'drenocortical activity in variou ways and procedures for suchconversions are now well-known. Thus, for example, from the productsaccording to the invention, one can prepare the 16u-methyl analogues ofcortisone, hydrocortisone, prednisone, prednisolone, the 9-halogenderivatives of such compounds, 9:1l-dichloro-ll-desoxpyredisolone and soon. As will be seen, the preparation of such compounds from the productsaccording to the invention may require the formation of a 3-keto group,introduction of unsaturation in Ring A, the introduction of the desiredsubstituent(s) in Ring C and the introduction of a hydroxy (or acy-loxy)group at position 21, all of which steps cm in principle be carried outby procedures hitherto used in the production of anti-inflammatory and/or adrenocortical hormones. For example, a compound of particularinterest is 16a-methyl-9a-fluoro-prednisolone acetate which can beprepared from a 3,8-acyloxy-l7es-hydroxy-l6wmethyl- SeregnQUU-en-ZO-oneby hydrolysis of the 3-acyloxy group, bromination followed byacetoxylation at the 21- position, formation of the 3-keto group,dibromination and dehydrobrominating in Ring A to give a A structure,epoxidising the 9(ll)-double bond and then reacting the 9,11-epoxygrouping with hydrogen fluoride to form16a-methyl-9a-fluoro-prednisolone acetate. If desired in any or all ofthe reactions of this sequence up to and including acetoxylation atposition 21, the double bond at the 9(11)-position can be protected bydichlorination, the chlorine atoms being subsequently removed, e.g. byhydrogenation.

We have found, according to the invention, that rearrangement ofl6:17-epoxy-16B-methyl-20-keto steroids of the 5C-SI'lS by means of anacid catalyst gives rise to either a 16-methylene compound or al6-methyl A compound (or mixtures thereof) according to the conditionsof rearrangement and that hydrogenation of either of such compounds inthe presence of certain catalysts tion under the conditions hereinafterset forth of the product of rearrangement of the epoxidegives one aproduct which whilst consisting essentially of a 16a-methyl compound maycontain some 16,8-metl1yl compound; the proportion of the 16fl-methylcompound in the product can however in general be kept low by soconducting the rearrangement that the product thereof is a A -cornpound.

According to the invention, therefore, there is provided a process forthe preparation of l7uhydroxy-l6amethyl-ZO-keto steroid of theSet-series in which a 16:17- epoxy-l6 8-methyl-20-keto steroid of the5:: series is subjected to rearrangement in a solvent medium in thepresence of an acid catalyst to form a product comprising a 16-methyleneor a A -steroid or a mixture thereof which product is then hydrogenatedin the presence of a palladium hydrogenation catalyst to yield a productcontaining a 17e-hydr0xy-l6u-methyl-20-keto steroid.

According to a further feature of the invention the 16: 17-epoxycompound is subjected to rearrangement in an ionising solvent medium,preferably a medium comprising a hydroxylic solvent such as a loweralcohol or an aqueous solvent medium.

ln the process of the invention, therefore, to obtain essentially16e-methyl compounds as distinct from 16B- methyl compounds it thus isfirstly essential that the hydrogenation step be conducted in thepresence of a palladium hydrogenation catalyst, other catalysts leadingessentially to lid-methyl compounds, and secondly Patented June 19, 1962v it is preferable to conduct the rearrangement so that the productthereof is substantially a A -compound.

The process of the invention can be illustrated diagrammatically asfollows, ring D only of the molecule being illustrated:

(lfi-methylene compound) (A -compound) The process of the invention willnow be described in greater detail:

1. PREPARATION OF 16:17-EPOXY -l6fi-METHYL-' ZO-KETO COMPOUNDS OF THESet-SERIES FROM THE CORRESPONDING A -COMPOUNDS This reaction is similarto the process described in British specification No. 805,497 andinvolves epoxidation with hydrogen peroxide under alkaline conditions,e.g. in the presence of sodium hydroxide. This reaction is in generalselective to double bonds conjugated with a keto group and hence willnot in general cause epoxidation of non-conjugated double bonds presentelsewhere in the molecule, e.g. at the 9(11)-position.

Representative compounds obtained in this step and useful as startingmaterial for the rearrangement stage, are for example compounds of thegeneral formula lcompound and subject the resultant A -l6:l7epoxide tohalogenation, since 9:11-dihalo compounds tend to be unstable to theconditions used to epoxidise the A -double bond.

For similar reasons, compounds in which X .is an 2. REARRANGEMENT OF THE16:17-EPOXY COMPOUND In principle, this rearrangement involves treatmentof the l6zl7-epoxide in a solvent medium with an acid catalyst, which ispreferably a strong or moderately strong acid. Suitable acids are, forexample, hydrogen bromide, hydrogen chloride, sulphuric acid, perchloricacid or formic acid. Mineral acids are generally to be preferred.

We find that where the rearrangement is carried out in the presence of asolvent medium of low ionising power a product is obtained onrearrangement which tends to have a relatively high proportion of16-n1ethylene compound. By the term solvent medium of low ionisingpower, we mean such media wherein the acid catalyst is not freelyionised. Preferred solvents for this purpose are the ethers, e.g.diethyl ether, di-isopropyl ether, especially the cyclic ethers, such asdioxan,tetrahydrofuran, etc. Where the rearrangement is carried out inother media of stronger ionising power, e.g. acetic acid, productscontaining lesser proportions of 16-methylene compound are in generalobtained.

Where the medium is one of comparatively strong ionising power i.e. onein which the acid used can freely ionise, the product of therearrangement is in general substantially the A -compound, which ispreferred for the purpose of the present invention. Such media includemedia consisting of or containing hydroxylic solvents e.g. methanol orethanol. The latter solvents may be admixed with other solvents notsubstantially reducing the ionising power of the medium but serving toimprove the solubility of the steroid therein, examples of such othersolvents being methylene dichloride, chloroform, dioxan, tetrahydrofuranetc. Media of high ionising power also include aqueous Water-misciblesolvents for the steroid, e.g. dioxan, tetrahydrofuran and acetic acid,the rearrangement in such cases being conveniently effected bydissolving the steroid epoxide in the Watermiscible solvent and addingaqueous acid to bring about the reaction.

In general, hydrogen bromide is the preferred acid for effecting therearrangement as it appears to provide the most consistent results ofacids so far examined. The reaction is conveniently carried out attemperatures of between 1530 C. The course of the reaction is bestfollowed by observation of the change in specific rotation of thereaction mixture since the rotation of the desired product is ingeneral, lower than that of the starting epoxide or any side products. v

If the product of the rearrangement is a mixture of A and 16-methylenecompound this can be separated e.g. by fractional crystallisation.However the A compound can if desired be readily freed from 16-methylenecompound by'taking advantage of the fact that the latter is more readilyD-homo-annulated than the A -compound, the A -compound thus being easilyseparated from the resultant mixture; Thus, for example, treatment ofthe mixture of lG-methylene compound and AIS-COKE- pound with borontrifiuoride in a solvent, e.g. dioxan, tetrahydrofuran etc. under mildconditions efiects substantially only D-homo-annulation of the16-methylene compound.

16-methylene compounds can be conveniently distinguished from A-compounds by comparison of infra-red spectra. In particular the16-methylene compounds possess a marked band at about 910 cm.

5 3. HYDROGENATTON OF THE PRODUCT OF THE REARRANGEMENT STAGE 2 TO Al6-METHYL COMPOUND The hydrogenation is carried out using a palladiumcatalyst.

Where the hydrogenation is efiected upon compounds also possessing adouble bond in the 9(ll)-position, it is generally best to carry out thereaction under neutral or basic conditions, conveniently in the presenceof an organic base e.g. pyridine, N-methyl-morpholine and collidine,relatively strong bases such as triethylamine or triethanolarnine beingpreferred. Supported palladium catalysts, e.g. using charcoal, calciumcarbonate or kieselguhr as supports are convenient or alternativelypalladium metal can be used. Acidic conditions may also be used but withincreasing tendency to formation of undesired byproducts.

The hydrogenation is conveniently conducted in an inert solvent medium,suitable solvents being for example tetrahydrofuran, dioxan, ethanol,ethyl acetate, tertiary butanol, methanol, and the like or mixtures ofone or more of these solvents. The reaction is further convenientlyefiected at atmospheric temperature and pressure.

The hydrogenation reaction may, of course, result in some change inother parts of the molecule. Thus for example, hydrogenation of9:1l-dichloro compounds with palladium catalysts in general gives riseto removal of the chlorine atoms with formation of a double bond. 9:11double bonds are, however, fairly resistant to hydrogenation and, underthe preferred condition of hydrogenation, given herein, are in generalunaffected.

Where the hydrogenation product contains some 168- methyl compound,separation may be effected as desired, e.g. by repeated crystallisation.It is sometimes found that slight modification of the molecule mayfacilitate this separation.

Thus, for example, 3B,l7a-dihydroxy-l6u-methyl-5apregn-9(l1)-en-20-onewhen contaminated by the 16sepimer, can be purified (a) bycrystallisation of the 3B, l7u-diol (rather than the 3-acetate) or (b)by the controlled treatment of the mixed S-acetates with borontrifluoride etherate in dioxan, which destroys the 16,8-methyl isomerfaster than the lcc-isomer.

Mot-compounds may be distinguished from 16/3-compounds in various ways,for example by difference in specific rotation, infra-red spectra andpaper chromatography. Thus in general the specific rotation of a16fi-compound is more positive than that of the corresponding16a-epimer; in paper chromatography a Mot-compound generally movesfaster than the corresponding 16,6-epimer.

In order that the invention may be well understood, the followingexamples are given by way of illustration only:

Example 1 (A) PREPARATION OF 3B-ACETOXY-lGB-METHYL-lfia:17a-EPOXY-5a-PREGN-9 (11) -EN20ONE 3fl-acetoxy l6methyl-5a-pregna-9(l1):l6-dien-20- one (70 g.) was dissolved in amixture of methanol (2.8 litres) and methylene chloride (350 ml.). 100vol. hydrogen peroxide (210 ml.) was added, followed by water (450 ml.)and 5 N aqueous sodium hydroxide solution (140 m1.) and the mixture wasstirred overnight at room temperature. A solid had precipitated by theend of the reaction period and the suspension was poured into water (5.0litres) and extracted with methylene chloride (4x750 ml.). water (4X 1.0l.) and the solvent distilled oil. The white solid residue was dissolvedin pyridine (70 ml.) and acetic anhydride (70 ml.) and heated for 0.5hour, on the steambath. Water' (250 ml.) was added and the product filtered E, washed with water (4x100 ml.) and dried at 100 in vacuo for 4hours to yield 3fl-acetoxy-16fl-methyl- 616a:l7a-epoxy-5a-pregn-9(11)-en-20-one (70 g.), M.P. 165-167. Theepoxide was recrystallised from methanol (1,700 ml.) filtered off,washed with a little methanol and dried at 100, in vacuo.

Wt.=61 g. (83% yield), M.P. 169-172 and u =+65.5 (c, 1 in crrcl (B)REARRANGEMENT OF 3fl-ACETOXY-16/3l\iETHYL- 16a :l7aEPOXY-5a-PREGN9 (11)EN20ONE 3/3-acetoxy 16,8 methyl l6oz2l7oc epoxy-M-preg'n-9(ll)-en-20-one g.) in acetic acid (110 ml.) was treated, with stirring,at room temperature, with 3.1% w/v hydrogen bromide in acetic acid (3.55ml.). The mixture was stirred for min. until the yellow colour developedand then anhydrous potassium acetate (0.15 g.) was added to dischargethe colour and stop the reaction. The precipitated solid was filteredoff, washed with water and dried in vacuo at 100.

Wt.=1.8 g. (36%), M.P. 180482", [a1 -69 (c, 1 in CHCl The filtrate wasconcentrated under reduced pressure until solid began to precipitate.The mixture was allowed to stand at room temperature for 2 hours, iso-The extracts were bulked, washed with lated by filtration, washed withdilute acetic acid, water and then dried at in vacuo.

Wt.=l.9 g. (38%), M.P. 178181, [aJ 68.5 (c, 1 in CHCl The filtrate wasdiluted with water (200 1111.), extracted with methylene chloride (4X25ml.) and the organic layers bulked, washed with water (1X50 ml.),saturated sodium bicarbonate solution (1X50 ml.) and water (1X50 ml.).The solvent was evaporated at reduced pressure and the residuerecrystallised from petroleum ether (B.P. 100-120).

Wt.=0.36 g., M.P. (166) -180", [a] 60 (c, 1 in CHCl The productcomprised about 40% of 16- methylene compound and about 60% of 16-methylA compound.

Example 2 3,8-acetoxy-16,8-methyl-l6a: l7a-ep oxy-S oc-preg'n-9( l 1en-ZO-one (1.0 g.) was treated as in Example 1(8) but with 56% aqueoushydriodic acid (0.04 ml.) instead of hydrobromic acid. The same product(0.56 g.) M.P. -182", [a]. 68 (c, 1 in CHCl was isolated.

Example 3 3fi-acetoxy-16B-methyl-16a: l7a-epoxy-5 a-pregn-S l len-20-one was treated with 4.02% w/v hydrochloric acid in acetic acid asabove in Example 1(8) and this gave the same product (0.61 g.) M.P.Nil-130, [0d -69 (c, l in CHCl Example 4 3 fi-acetoxy-l6B-methyl-16al7a-epoxy-5a-pregn-9( 1 1 en-20-one (0.94 g.) in methylene chloride (10ml.) was treated with 50% aqueous hydrobromic acid (10 ml.) at roomtemperature for 1 hour and gave a product (0.55 g.), M.P. 178482, [@1 70(c, 1 in CHCl believed to contain about 40% of ldiethylene compound andabout 60 of l6-methyl-A compound.

Example 5 Bfi-acetoxy-l6 8-methyl-l6a: 17Ct-BPOXY-5 u-pregn-9( 1 len-20-one (0.5 g.) in acetic acid (11 ml.) was treated yvith N sulphuricacid (1 ml.) and allowed to stand at room temperature for 1 /2 hours.The product (0.3 g.)

was isolated on working upM.P. 178l81, [a1

67 c, 1 in crici and contained about 70% of 16- rnethyl-A compound. 7

Example 6 3 ,B-acetoxy-l 6(3-methyl-16a: l7oz-epoxy-5'a-pregn-9( 1 len-20-one (0.5 g.) was dissolved in acetic acid (20ml) 7 containing 2drops of perchloric acid.

Time (mins.): a

The reaction was stopped by the addition of anhydrous potassium acetateand worked up in the same manner to yield a product (0.15 g.) havingM.P. 180-182" [041 -71 (0, 1 in CHCl Example 7 as shown by the constantsof the final product: M.P.

180-183", [00] 76 (0, 1 in CHCl The product contained about 70% ofl6-methylene compound.

Example 8 PREPARATION OF 3 9-ACETOXY-l7aHYDROXY-15a- METHYL- a-PREGN-Q(l1) EN-ZO-ONE A catalyst consisting of'l0% Pd/C (0.25 g.) wasprereduced in tetrahydrofuran (2 ml.) (9.7 ml. hydrogen absorbed over 30mins.) and the .re-arrangement product OLE-Example 1(B) (1.0 g.) wasthen added in tetrahydrofuran (7 ml.) and triethylamine (0.15 ml.). Afurther 1 ml. of tetrahydrofuran was used as washings and thehydrogenation commenced. The theoretical quantity of hydrogen (62.8 ml.at 22) was absorbed in about 4 hours and the catalyst was then filteredoff, washed with tetrahydrofuran (4X5 ml.) and the filtrate evaporatedunder reduced pressure to near dryness and water (50 ml.) added. Thesolid was filtered off, washed with water and dried at 100 in vacuo.

Wt.=0.95 g., M.P. 158-163 The steroid (0.95 g.) was dissolved inmethanol, hot filtered, evaporated to about 10 ml. and allowed tocrystallise. This product (M.P. 162-166) was recrystallised frompetroleum ether (B.P. 100-120") ml), allowed to stand overnight at roomtemperature, filtered ofi, washed with a little petroleum ether (B.P100-120) and dried at 100 in vacuo.

Wt.=0.58 g., M.P. 165170, [a] 17.4 (c, 1 in CHCl Example 9 Example 10was repeated but omitting the triethylamine and using steroid (0.5 g.),tetrahydrofuran (6.0 ml.) and pro-reduced 10% Pd/C catalyst (0.25 g.).Hydrogenation was complete in about 1 hour. The product was isolated bytotal precipitation from water.

The re-arrangement product of Example 1(B) (0.5 g.)

in acetic acid (8 ml.) and methylene chloride (2 ml.) was added to acatalyst of 10% Pd/C (0.25 g.) which had been pre-reduced in acetic acid(2 ml.). The hydrogen uptake was complete after 1.5 hours and theproduct was 5 worked up as in Example 10.

Wt.=0.47 g., M.P. 167-172 0., [021 15 (0, 1 in CHCl Example 11 103/3-ACETOXY-17a-HYDROXY-16-}IETHYLENE-5a-PREGN- 9 (11)EN20-ONE 3Bacetoxy 16a217a epoxy 16,8 methyl 5ozpregn-9(l1)-en-20-one (6.0 g.) insolution in pure dioxan (50 ml.) was treated at room temperature with a2.2% 15 (w/v) solution of hydrogen bromide in acetic acid (1.0 ml.). Thespecific rotation of the steroid fell from [ab +63 and became steady at[00] 36 in 12 minutes. Crystals began to separate after 13 minutes andafterlS minutes the suspension was diluted with water to 400 20 ml. Thecrystalline product (5.9 g.), M.P. l78-l80, [ab 80 (c, 1.4 in CHCI wasfiltered off, washed with water and dried at 0.1 mm./100 C. for 3.5 hr.crystallisation of the crude product (4.0 g.) from ethyl acetate (20ml.) gave the 16-methylene-compound (2.89 g.) as needles, M.P. l81l82,[ab 81 (c, 1.15 in CHCI (Found: C, 74.8; 1 1, 8.9. C I-1 0 requires C,74.7, H, 8.9%.) Other similar experiments were carried out as in thefollowing table,

3B-ACETOXY'17aHYDROXY-1G-METHYLENE-iiu-PREG- NANE-ll,20-DIONE 3Q acetoxy160x170: epoxy 16B methyl 5apregnane-11,20-dione (500 mg.) in puredioxan (25 ml.) was treated at room temperature with a 2.2% solution ofhydrogen bromide in acetic acid (1.0 ml.). The specific rotation of thesteroid fell from +65 and became steady at +2 in 40-45 minutes. Aftermin. the solu- 50 tion was poured into water (170 ml.) and theprecipitated product (450 mg), [ab 25 (c, 1.4 in CHCI was collected byfiltration and washed with water, and dried. crystallisation fromacetone-hexane, gave the 16-methylone compound (174 mg.) [M -42 (c, 1.28in CHC13)- Found: C, 71.1; H, 8.5; C H O require C, 71.6; H, 8.5%.

Example 13 (A) 3B-ACETOXY-9a :1'1B-DICHLORO-16a :17a-EPOXY-1 6B-METHYL-5 a-PREGNAN-ZO-ONE 3,8 'acetoxy 16 8 methyl l6azl7a epoxy 5apregn-9(l1)-en-20-one (2.8 g.) in chloroform (60 ml.) was treated with asolution of chlorine (0.44 g., 1 equiv.) in carbon tetrachloride (11.2ml.). The yellow colour was discharged immediately. After standing for10 min. the solution was washed successively withdilute aqueous sodiumthiosulphate and water. The organic solution was dried (MgSOQ and. thesolvent was removed to leave a pale yellow crystalline solid (3.28 g.,99%), M.P. 184- l88 Crystallisation from acetone gave 3B acetoxy 9a:1l,3dichloro 16aZ17 x epoxy 16,8 methyl 5ozpregnan-ZO-one (3.02 g., 91%),M.P. 193-195 (Kofi), [04] +58 (0, 1.2 in CHClg). (Found: C, 63.06; H,7.64; Cl, 15.65; C H O Cl requires C, 62.96; H, 7.5; C1,15.5%.)

(B) PREPARATION OF 35-ACEIOXY-9a:llfi-DICHLORO- 1 7aHYDROXY-1G-METHYLENE-Sa-PREGNAN-QO-ONE (i) Indioxan.3B-acetcxy-9a:11B-dichloro-16u:17aepoxy-16,8-1nethyl-5a-pregnan-20-one(500 mg.) in pure dioxan (25 ml.) was treated at room temperature with a2.2% solution of hydrogen bromide in acetic acid (1.0 ml.). The specificrotation of the steroid fell from +53 and became steady at +0.5 in 35-40min. After 46 min. the solution was poured into water, and theprecipitated product (479 mg), [(11 .23.5 (c, 1.0 in CHCl was collectedby filtration, washed with water, and dried. Crystallisation fromacetone-hexane gave the 16-methylcue-compound (292 mg), M.P. 189(decomp), [a1 29 (0, 1.48 in CHCI (ii) In acetic acid.The epoxide (8.9g.) was dissolved in a mixture of methylene chloride (40 ml.) andglacial acetic acid (340 ml.) and treated with a solution of hydrogenbromide in glacial acetic acid (8.9 ml. of a solution containing 2.2 g.HBr in 100 ml). The mixture was kept at room temperature until therotation had fallen to a constant value (ca. 15 min); the colour of thesolution was a greenish-blue. The mixture was poured into a large volumeof 1% sodium acetate solution. The prodnot was extracted with methylenechloride, the organic layer was washed successively with water, aqueoussodium bicarbonate and water, dried (MgSO and the solvent removed togive a yellow solid, This product was crystallised from acetone-hexaneand dried at 80-90 in vacuo furnishing 3 fl acetoxy-9u 1 1Bdichloro- 1S-methylene-l7a-hydroxy-5a-pregnan-20-one (7.4 g., 83%), M.P. 193-l95[oc] 34 (0, 0.94 in CHCI (Found: C, 63.1; H, 7.5; Cl, 15.2. C H O Clrequires C, 63.0; H, 7.5; Cl, 15.5%.)

Example 14 (A) TREPARATION OF THE 16 :17-PYRAZOLINE OF 33-ACETOXY-Fm-PREGN-lS-ENE-ll :ZO-DIONE (i) Use of N:N' dinz'tr0s0-N:N'dimezhylzerephzhalamide (N.N.P.).3fi-acetoxy-5a-premi-l6-ene-1l:20 dione(200 g.) was dissolved in methylene chloride (3.1) in a 10 l. three-neckflask fitted with thermometer, dropping funnel, nitrogen inlet andstainless steel stirrer. N.N.'P. reagent (200 g.) was added withstirring and the total solution brought to 27 40% aqueous sodiumhydroxide solution (1.75 1'.) was run in over two hoursinitiallymaintaining the temperature at 1".7" then, when reaction set in, coolingto maintain the temoerature below 30, Ice Water (4 l.) was added and theresulting two phase mixture stirred while a brisk nitrogen stream wasbubbled through to remove excess diazomethane. When the colour of thesolution indicated that diazomethane was absent, the two phases wereseparated and the aqueous phase extracted with methylene chloride (3x400 ml.), the bulked methylene chloride extract washed with water (3X500 ml.) and taken to dryness finally under reduced pressure. The whitesolid product was broken up under petroleum (B.P. 40-60", 600 ml.),filtered and dried at 60/ 0.1 mm. for 3 hours, yield 191 g., M.P.'176176.5 dec., [a] =|11l (c, 1 in Cl-lCl (ii) UsingN-nitroso-N-methylurea.3fi-acetoxy-5apregn-16-ene-11:20-dione (200 g.)was dissolved in methylene chloride (2 l.) and cooled to in a 5 1.threenecked flask fitted with stirrer, thermometer, nitrogen inlet anddropping funnel. The solution was stirred and cooled to 5 whilenitrosomethylurea (130 g. moisture )was added.

Potassium hydroxide (45% solution, 200 ml.) was run in with stirring atsuch a rate as to keep the temperature between 5 and 0 (ca. 30-45 min.)then the reaction mixture was allowed to warm to over 90 min. and icewater' (1.5 1.) added. Nitrogen was bubbled through the reaction mixtureuntil the diaZo-methane colour was removed. The two layers wereseparated and bath for 30 minutes.

10 worked up as under (A) above. Yield 200.3 g., M.P. 175178 dec., [a]=-|ll1 (c, 1 in CHCl (B) PREPARATION OF 3FACETOXY-l6-METHYL 5u-PREGN-16-ENE-11 20-DIONE The 16:17-pyrazoline of3,8-acetoxy-5aepregn-l6-ene- 11:20 dione (200 g.) was added todiethylene glycol (660 ml.) maintained at 187-* -2 with stirring over 8minutes. The solution which turned yellow and eifervesced during theaddition was held at this temperature for a further 10 minutes, cooledrapidly to ca. and diluted carefully with water (1 litre). Thesuspension was allowed to cool to room temperature overnight and thecrystals were collected on a sintered plate, washed thoroughly withwater and dried at 0.1 mm. for 4 hrs.

This crudeproduct was dissolved in methanol (3.2 l.) and allowed to coolto 0 overnight. The crystals were collected by filtration, washed withice-cold methanol (300 ml.) and dried at 60/0.1 mm. for 3 hrs. Yield 116g., M.P. 169170, [cc] =+25 (c, 1 in CHCI (C) 3B-ACETOXY-16a.:17a-EPOXY-lGB-lllE'lHYLfia- PREGNANEdl 20-DIONE 5 N-sodium hydroxidesolution (20 ml.) was. added dropwise to a stirred mixture of3fi-acetoxy-16-methyl- 5a-pregn-16-ene-11:20 dione (10 g.), methylenechloride (50 ml.), methanol (400 ml.), 100 volume hydrogen peroxide (30ml.), water (100 ml). The mixture was stirred at room temperatureovernight. Addition of water (750 ml.), extraction with methylenechloride (4x200 ml.) washing the extract with water (4x800 ml.) andremoval of the solvent in vacuo gave a crude product (9.2 g.). This wasre-acetylated by heating with acetic anhydride (10 ml.) and pyridine (10ml.) on the steam The mixture was diluted with water (50 ml.) filteredand solids washed with water (4X20 ml.) and dried at 100 C. in vacuo.The crude product (9.8 g.), M.P. 182-192 C. was recrystallised fromindustrial alcohol (50 ml.) to give the pure epoxide (7.1 g.) M.P.192196 C., [aJ +74 (0, 1.075. in CHCl (D) REARRANGEMENT 02B3BACETOXY-1SaJJ'Ia-EPOXY- 165-l\1'ETHYL-5a-PREGNANE-11,20-DIONE A 3.1%solution of hydrogen bromide in acetic acid (3.6 ml.) was added to astirred solution of 3p-acetoxyl-6oa117a epoxy 16p methyl 50c pregnane11:20- dione (5 g.) in acetic acid (100 ml). After stirring for 15minutes at room temperature the mixture was decolorised by addition ofanhydrous potassium acetate (0.1 g.) and water ml.) was added. After afurther 15 minutes stirring the solid product was collected byfiltration, washed with water (4x50 ml.) and dried at 100 C. in vacuo.Yield, 3.92 g. (second crop 0.58 g. from the mother liquors).Recrystallisation from cyclohexane gave a product, M.P. 186188.5 0.,[0:1 50.9 (c, 1.178 in CHCl containing a substantial proportion of16-methylene compound.

(E) HYDROGENATION WITH PALLADISED CHARCOAL IN TETRAHYDROFURAN Thematerial obtained according to (D) (2 g.) was shaken with hydrogen andpro-reduced 10% palladised charcoal (0.6 g.) in tetnahydrofuran (100ml). After 1 hours hydrogenation was very slow (128 ml. taken up, ca. 1mole) and the mixture was filtered and evaporated in vacuo.crystallisation from petrol (B.P. 6080) gave a product (1.14 g.) [ab+7.1". Part of this (0.5 g.) was re-hydr-ogenated by shaking with 50% byweight of 10% palladised charcoal in tetrahydrofuran (5 vols). The finalproduct crystallised from cyclohexane to give 0.29 g., M.P. 163166 [1x1+27.6 (c, 1.197 in CHCl Example 15 (a) To a solution of3fi-acetoxy-16fi-methy1-16a}17atated by the further addition of watertotalling 480 ml. The product was collected, washed with water anddried, (19.5 g.), [a1 51.2 (CHCl Infra-rcd'ex-aminationsuggested that itcontained about 80% of the 16- methyl-lS-en and 20% of the 16-methylenecompound. The product was recrystallised twice from methanol to givepure- 3-acetoxy-17a-hydroxy-l6-methyl-5a-pregna- 9(11): 15dien-20-one,M.P. 184-188, [@1 9 60 (CI-I01 The foregoing experiment was repeatedwith different solvent/ acid combination and the results were asfollows:

Acid Solvent Product H01 Tetrahydroiurau containing 16 methylene com 18%Acetic Acid. 1 poun 11 N aqueous HBL. Tetranydroiuran containingEssentially A 10% Acetic Acid. compound. 11 N aqueous HGlTetrahydroiuran containing Essentially A 5% Acetic Acid. compound.

(b) A solution of the same l6azl7a-oxide as in (a) (30 g.) intetrahydrofuran (120 ml.) and acetic acid (6 ml.). was stirred at 19 andtreated with concentrated (11 N) hydrochloric acid (12 ml.). After 1.5hours the reaction mixture was poured into an excess of water containinga little sodium acetateand the product collected, washed with water,dried, and recrystallised twice from methanol afiording the16-mcthyl-15-ene compound (14.44 g., 48.1%) M.P. 184-189, a1 60.2 C, 1.0in CHCla), 46.4 (C, 1.0 in dioxan).

(c) palladised charcoal (1.25 g.) in tertiary butanol (20 ml.) waspre-reduced in hydrogen and a solution of the16-methyl-15-ene compoundfrom (b) (2.5 g.) in tertiary butanol (100 ml.) and methylene chlorideml.) added. The mixture was hydrogenated over 2 hours, the catalystremoved by filtration and the filtrate evaporated to dryness giving acrystalline residue The epoxide (600 mg), in purified tetrahydrofuran 10ml.), was treated with 2.2% hydrogen bromide in acetic acid (0.2 ml.).The rotation of the solution fell from [0:1 +60 to [ari in 80 min, andthen remained unchanged. After. 2 hr. the solution was poured intowater,and'the precipitated product (560 mg.) [mi '79.4 (CHCl was collected byfiltration, washed with 7 water, dried, and recrystallised from ethylacetate, to give the l-methylene-compound (365' mg., 61%), M.P. 179-1822[a 5'- -80.4 (c, 1.52 in CHCl;;).' 7

Example 17,

(A)- PREPARATIONIOF 3B-ACETOXY-l7a HYDliOXY-lfi- METHYL-5d-PREGNA-9 (11),15-D1EN-20-ONE The excess of acetic anhydride was decomposed by theaddition of a little'water and the steroid precipi- 12 bromide in aceticacid (3.2 N; 1.0 ml.). The rotation fell from zx =+2.0 to oc :-1.25 in22 hr., and remained steady for, a further 2 hrs. The solution was thenshaken with water (200 ml.) and'methylene chloride (50 ml.), and theaqueous layer was extracted with more methylene chloride (3 x10 ml.).The combined methylene chloride extracts were washed with aqueous sodiumhydrogen carbonate and water and dried over magnesium sulphate. Removalof the solvent from the dried extract in vacuo left a residue (922 mg),[041 S9.5 (c, 0.86 in CHCl which, from its infrared spectrum, containedca. 40% of 3f3-acetate.

The solid was heated at 100 for 30 min. in dry pyridine (10 ml.) andacetic anhydride (10 ml), and the mixture was poured into ice-Water (200ml.). The precipitated product (952 mg), M.P. 158-166", [a] 55 (c, 0.99in CHCl was collected by filtration. crystallisation of part (800 mg.)from ethyl acetate gave needles (516 mg.) of3fi-acetoxy-l7a-hydroxy-l6-methyl- 5ot pregna-9(1l),l5-dien-20-one, M.P.179-182, [i11 63.5 (c, 0.93 in CHCI containing some of the 16- methyleneisomer.

(ii) 16a,l7a-epoxy-3fl-hydroxy-lofi methyI-Suregn- 9(ll)-en-20-one (5.0g.) was treated as in the preceding experiment (i) to give, afteracetylation, a crude product (5.824 g.), [0L1]; -33 (CHClCrystallisation from ethyl acetate gave impure 16- rnethyl-A -compoundin two crops, the first crop (3.30 g.) having M.P. 179-182", [aJ 64.3(c, 1.5 in CHCl [041 -43.5 (c, 2.0 in dioxan), and the second crop 573mg), Mr. 178-182, [04] 64.1 (c, 1.92

inCHCI The mother liquor material was separated into hexane-insoluble(460 mg.) and hexane-soluble (1.2 g.) fractions. The insoluble fractioncrystallised from methanol to give purer 16-methyl-A -compound (200 mg),[4x1 60.6 (c, 1.56 in CHClg).

' The impure l6-methyl-A -compound (3.0 g.) from the first crop,containing some of the 16-methylene isomer, in solution in pure dioxan(150 ml.) was treated with boron trifiuoride etherate (3.0 ml.) at roomtemperature. During min. the rotation of the solution changed steadilyfrom [M 42.5 to [a] 28, and was continuingto rise. D-homoannulation ofthe 16- methyiene compound is complete under these conditions. Thesolution was then poured into ice-water, (1200 ml), and after 2 hrs. theprecipitated product (2.91 g.), [(21 -42 (CHCI was collected byfiltration, washed with water, and dried. One crystallisation fromhexane (1000 ml. cone. to 400 ml.) gave the 16-methyl-A -compound asneedles (1.98 g.), M.P. 182l84 [a] 6 3 (c, 1.24 111 CI-ICI Furthercrystallisations from hexane, then from methanol gave the analyticalsample (1.10 g.), M.P. 183.5-185", [11] --61.4 V (c, 1.22 in CHCl(found: C, 75.0; H, 9.0; C H O requires C, 74.6; H, 8.9%). (B)HYDROGENATION on ee-non'roxx-l'm-nynaoxr- 1 6-METHYL-5 a-PREGNA-Q (1'1),15-DIEN-20-ONE 3,8 -acetoxy-l7a-hydroxy-l6-methyl 5a pregna-9(ll),15-d1en-20-one (152 mg.)'in ethyl acetate (15 ml.) was reduced over a 5%palladium-on-charcoal catalyst (56 mg). The hydrogenation ceased afterthe uptake of v only 0.8 mol. of hydrogen in 3 hours; The product,

(i) 3B-acetoxy-16a,l7a-epoxy-l6fl-methyl 50c pregn- 9(ll)-en-20-one (1.0g.) in methanol (20 ml.) and methylene chloride (11 ml.) was treatedwith hydrogen worked up in'the usual way, had [aJ +10 (c, 1.12 indioxan). Tnree crystallisations from petroleum ether gave a mixture (46mg.) of 16aand 16,8-methyl isomers M.P. l71-174, [aJ +7.5? (c, 2.36 indioxan) containing -90% of the former.

The crudeacetate (260 mg.) from a similar experiment was boiled underreflux for 3 hours with potassium bicarbonate (.155 mg.) inmethanol (8ml.) and water (3 ml.). The. 3,17-diol (168 mg), [a1 +8.5(c, 1.1

in dioxan), which separatedwas filtered from the hot solution, washedwith hot aqueous methanol and dried at /0.5 mm. Four jcrystallisationsfrom, aqueous methanol gave a puresample of 3,8,17a-dihydroxy-16a- 13methyl-5a-pregn-9(11)-en-20-one (68 mg), M.P. 233- 237, [cc] +2.8 (c,0.6 in dioxan).

The recrystallised diol (:30 mg.) was acetylated with acetic anhydrideand pyridine at 100 for 15 min., and the crude product was crystallisedfrom petroleum (B.P. 60-80") to give3B-acet0xy-17a-hydroxy-16a-methyl-5apregn-9(11)-en-20-one (46 mg), M.P.175-177", [11] +3 (c, 2.0 in dioxan).

Example 18 PREPARATION OF PURE 3E-ACETOXY-l7cr-HYDROXY-lfizz-METHYL-iiwPREG-Q (11)-EN-20-ONE BY PARTIAL D-HOMO-ANNULATION OFMIXTURES OF 16a- AND 165 ll'lETHYL 3B ACETOXY 17a HYDROXY 5a- PREGN-Q(11)-EN-20ONE A mixture of l6rxand16fi-methyl-3fi-acetoxy-l7a-hydroxy-5a-pregn-9(11)-en-20-one (265 mg.)(ca. 1:1) in dioxan (10 ml.) was treated with boron tn'fluoride etherate (0.2 ml.) and stored at room temperature. After 15 min., when therotation was constant at +4.9, the mixture was diluted with water,extracted with ether, washed with dilute sodium bicarbonate solution andWater, and evaporated in vacuo to dryness, to give a mixture of crystalsand oil (270 mg). Two crystallisations from petroleum-ether gave3/3-acetoxy-17a-hydroxy-16a-methyl-5 -pren-9(1l)-en-20-one (50 mg.) asneedles, M.P. 177-180 after previous sweating, [aJ +4.1 (c, 2.21 indioxan).

Example 19 35,171i DIHYDRXY-16a ME1HYL-5a-PREGN-Q (11) EN-20-ONE3,6-acetoxy-17a-hydroxy-L6-methylene-5 a-pregn-9 1 1 en-20-one (5.0) inethyl acetate (50 ml.) was added to a pre-reduced suspension ofpalladium-on-charcoal (1.66 g.) in ethyl acetate (200 ml.). One mol. ofhydrogen was taken up in 9 min. and uptake had virtually ceased at 1.13mol. after 30 min. The product, isolated in the usual way, had [ab +16.5(c, 1.57 in dioxan. The infrared spectrum and optical rotation indicatedthe presence of ca. 60-70% of the lfioz-isomer.

The hydrogenation product (1.0 g.), in methanol (30 ml.), was refluxedfor 3 hours with a solution of potassium bicarbonate (600 mg.) in water(12 ml). The reaction mixture was filtered hot, furnishing white cubiccrystals (583 mg., 65%), M.P. 215-230", [u] +1.3 (c, 1.58 in dioxarl).crystallisation from aqueous methanol gave3,8,17a-dihydroxy-16cz-methyl-5a-pregn-9( 1 1)-en-20- one (351 mg. 40%),M.P. 225-235", [a] +l (c, 11.10 in dioxan).

The filtrate from the above hydrolysis was allowed 14 to cool, yieldingneedles (190 mg.), M.P. 201-0, [a] +29 (c, 1.3 in dioxan), which wereidentified as consisting predominantly (ca. of 3 ,B,l7a-dihydroxy16fi-methyl-5a-pregn-9(11)-en-20-one.

A portion (202 mg.) of 3B,17a-dihydroxy-16m-methyl-5a-pregn-9(l1)-en-20-one, prepared as above, was acetylated with aceticanhydride in pyridine for 6 hours at room temp. The reaction mixture wasworked up in the usual way and crystallised from petroleum ether to givea slightly impure sample of 3fi-acetoxy-17a-hydroxy-16a-methyl-5a-pregn-9(1l)-en-20 one (192 mg, 87%), M.P. [a] +1 (c, 2.2 in dioxan.)

We claim:

1. A process for the preparation of a product which is a17u-hydroxy-16-methyl-20-keto-steroid of the Six-series in which the16a-methyl isomer predominates, which process comprises contacting a16:17-epoxy-16B-methyl- 20-keto steroid of the 5 ct-series with an acidcatalyst in an ionising solvent medium to rearrange said last-mentionedcompound to produce a mixture of l6-methyleneand A -compounds in whichthe A -compound is in excess, contacting said mixture with borontrifluoride to effect D-homo-annulation of the 16-methylene compoundwithout changing said A -compound, separating the A -compound from theresultant mixture, and hydrogenating the separated A -compound in thepresence of a palladium hydrogenation catalyst.

2. A process for the preparation of a product which is a17a-hydroxy-16-methyl-A -20-keto steroid of the 5::- series in which the16a-methyl isomer predominates, which process comprises contacting a16:17-epoxy-16B- methyl-A -20-keto steroid of the 5 a-series with anacid catalyst in an ionising solvent medium to rearrange saidlast-mentioned compound to produce a mixture of 16- methylene and A-compounds inwhich the A -compound is in excess and hydrogenating saidmixture in the presence of an organic base and a palladium hydrogenationcatalyst.

3. A process as claimed in claim 2 in which said organic base istriethylamine.

References Cited in the file of this patent UNITED STATES PATENTS2,947,765 Julian et a1 Aug. 2, 1960 2,954,386 Beyler Sept. 27, 19602,960,503 Weinstock et al Nov. 15, 1960 2,963,495 Fried et al Dec. 6,1960 OTHER REFERENCES Nomine et al.: Tetrahedron, vol. 8, 217-220(1960).

1. A PROCESS FOR THE PREPARATION OF A PRODUCT WHICH IS A 17 A-HYDROXY-16-METHYL-20-KETO-STEROID OF THE 5A-SERIES IN WHICH THE 16A-METHYL ISOMER PREDOMINATES, WHICH PROCESS COMPRISES CONTACTING A 16:17-EPOXY-16B-METHYL20-KETO STEROID OF THE 5A-SERIES WITH AN ACID CATALYST IN AN IONISING SOLVENT MEDIUM TO REARRANGE SAID LAST-MENTIONED COMPOUND TO PRODUCE A MIXTURE OF 16-METHYLENE- AND $15-COMPOUNDS IN WHICH THE $15-COMPOUND IS IN EXCESS, CONTACTING SAID MIXTURE WITH BORON TRIFLUORIDE TO EFFECT D-HOMO-ANNULATION OF THE 16-METHYLENE COMPOUND WITHOUT CHANGING SAID $15-COMPOUND, SEPARATING THE $15-COMPOUND FROM THE RESULTANT MIXTURE, AND HYDROGENATING THE SEPARATED $15-COMPOUND IN THE PRESENCE OF A PALLADIUM HYDROGENATION CATALYST. 